Vitamine C: improving endothelial function

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Vitamine C: improving endothelial function

Bericht door Willy » zo aug 24, 2003 4:33 pm

<H4>Endothelial dysfunction in human disease</H4><I>
Drexler H, Hornig B. Medizinische Hochschule Hannover, Germany.</I><BR>
The vascular endothelium plays a key role in the local regulation of vascular tone by the release of vasodilator substances (i.e. endothelium-derived relaxing factor (EDRF = nitric oxide, NO) and prostacyclin) and vasoconstrictor substances (i.e. thromboxane A2, free radicals, or endothelin). Using either agents like acetylcholine or changes in flow to stimulate the release of EDRF (NO), clinical studies have revealed the importance of EDRF in both basal and stimulated control of vascular tone in large epicardial coronary arteries and in the coronary microcirculation. The regulatory function of the endothelium is altered by cardiovascular risk factors or disorders such as hypercholesterolemia, chronic smoking, hypertension or chronic heart failure. Endothelial dysfunction appears to have detrimental functional consequences as well as adverse longterm effects, including vascular remodelling. Endothelial dysfunction is associated with impaired tissue perfusion particularly during stress and paradoxical vasoconstriction of large conduit vessels including the coronary arteries. These effects may cause or contribute to myocardial ischemia. Several mechanisms may be involved in the development of endothelial dysfunction, such as reduced synthesis and release of EDRF or enhanced inactivation of EDRF after its release from endothelial cells by radicals or oxidized low-density lipoprotein (LDL). Increased plasma levels of oxidized LDL have been noted in chronic smokers and are related to the extent endothelial dysfunction, raising the possibility that chronic smoking potentiates endothelial dysfunction by increasing circulating and tissue levels of oxidized LDL. In heart failure, cytokines and/or reduced flow (reflecting reduced shear stress) may be involved in the development of endothelial dysfunction and can be reversed by physical training. Other mechanisms include an activated renin-angiotensin system (i.e. postmyocardial infarction) with increased breakdown of bradykinin by enhanced angiotensin converting enzyme (ACE) activity. There is evidence that endogenous bradykinin is involved in coronary vasomotor control both in coronary conduit and resistance vessels. ACE inhibitors enhance endothelial function by a bradykinin-dependent mechanism and probably also by blunting the generation of superoxide anion. Endothelial dysfunction appears to be reversible by administering L-arginine, the precursor of nitric oxide, lowering cholesterol levels, physical training, antioxidants such as vitamin C, or ACE inhibition.
Source: http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract
<H4>Reversibility of coronary endothelial vasomotor dysfunction in idiopathic dilated cardiomyopathy: acute effects of vitamin C</H4><I>
Richartz BM, Werner GS, Ferrari M, Figulla HR. Friedrich-Schiller-University Jena, Jena, Germany.</I><BR>
In patients with idiopathic dilated cardiomyopathy, endothelium vasomotor function is disturbed. Increased oxidative stress and the consecutive formation of oxygen free radicals have been implicated as one possibility for this observation, suggesting that nitric oxide (NO) is inactivated by oxygen free radicals. We tested the hypothesis that the antioxidant, vitamin C, may improve endothelial function in idiopathic dilated cardiomyopathy. In 11 patients, the endothelium-dependent vasomotor response of the left anterior descending coronary artery to intracoronary acetylcholine (ACh) infusion (1/2 x 10(-6) mol/L, 1/4 x 10(-5) mol/L; respectively) was determined before and immediately after intravenous infusion of 3 g of vitamin C. Coronary cross-sectional diameter was obtained by quantitative coronary angiography, average peak velocity was measured by an intracoronary Doppler flow wire, and coronary blood flow (CBF) was calculated. Maximum cross-sectional diameter was determined after administration of nitroglycerin. Dose-dependent ACh showed a decrease in cross-sectional diameter (-5% to -7%, p <0.05) and an increase in average peak velocity (+16% to +25%, p <0.05); the CBF was unchanged (+1% to -2%, p = NS). After vitamin C infusion, the cross-sectional diameter increased in a dose-dependent manner from +11% to +15%, the average peak velocity increased from +20% to + 41% (p <0.05), and the CBF increased from +38% to + 82% (p <0.01, p <0.001, respectively). Thus, patients with idiopathic dilated cardiomyopathy had endothelial dysfunction, and administration of vitamin C reversed endothelium-dependent dysfunction.
Source: http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract
<H4>Vitamin C inhibits endothelial cell apoptosis in congestive heart failure</H4><I>
Rossig L, Hoffmann J, Hugel B, Mallat Z, Haase A, Freyssinet JM, Tedgui A, Aicher A, Zeiher AM, Dimmeler S. Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Germany.</I><BR>
BACKGROUND: Proinflammatory cytokines like tumor necrosis factor-alpha and oxidative stress induce apoptotic cell death in endothelial cells (ECs). Systemic inflammation and increased oxidative stress in congestive heart failure (CHF) coincide with enhanced EC apoptosis and the development of endothelial dysfunction. Therefore, we investigated the effects of antioxidative vitamin C therapy on EC apoptosis in CHF patients. METHODS AND RESULTS: Vitamin C dose dependently suppressed the induction of EC apoptosis by tumor necrosis factor-alpha and angiotensin II in vitro as assessed by DNA fragmentation, DAPI nuclear staining, and MTT viability assay. The antiapoptotic effect of vitamin C was associated with reduced cytochrome C release from mitochondria and the inhibition of caspase-9 activity. To assess EC protection by vitamin C in CHF patients, we prospectively randomized CHF patients in a double-blind trial to vitamin C treatment versus placebo. Vitamin C administration to CHF patients markedly reduced plasma levels of circulating apoptotic microparticles to 32+/-8% of baseline levels, whereas placebo had no effect (87+/-14%, P<0.005). In addition, vitamin C administration suppressed the proapoptotic activity on EC of the serum of CHF patients (P<0.001).
CONCLUSIONS: Administration of vitamin C to CHF patients suppresses EC apoptosis in vivo, which might contribute to the established functional benefit of vitamin C supplementation on endothelial function.
Source: http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract
<H4>Randomized, double-blind, placebo-controlled study of ascorbate on the preventive effect of nitrate tolerance in patients with congestive heart failure</H4><I>
Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y. Department of Cardiology, KINU Medical Association Hospital, Mitsukaido, Ibaraki, Japan. wata-h@xa2.so-net.or.jp</I><BR>
BACKGROUND: Reduced cGMP production caused by increased superoxide has been proposed as a mechanism of nitrate tolerance during continuous nitrate therapy. This study was designed to evaluate the effects of ascorbate, an antioxidant, on the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure. METHODS AND RESULTS: Twenty patients with congestive heart failure were randomized to receive intravenous infusion of nitroglycerin concomitantly with placebo (placebo group, n=10) or intravenous ascorbate (vitamin C group, n=10). After baseline measurements were obtained, dose titration was started by the infusion of nitroglycerin at a rate of 0.5 microg/kg per minute (titration period). Measurements of hemodynamic parameters and blood sampling were performed serially at 0, 6, 12, 18, and 24 hours after the titration period. At baseline, mean pulmonary artery pressure (MPAP, mm Hg), mean pulmonary capillary wedge pressure (PCWP, mm Hg), plasma vitamin E level (micromol/L), and platelet cGMP level (pmol/10[9] platelets) were comparable in the two groups (placebo group: MPAP, 48+/-6; PCWP, 24+/-4; cGMP, 0.76+/-0.12; vitamin E, 18.2+/-1.2; vitamin C: MPAP, 49+/-7; PCWP, 24+/-4; cGMP, 0.71+/-0.16; vitamin E, 18.6+/-1.3). In both groups, at 6 hours after the titration period, MPAP and PCWP were significantly decreased (placebo group: MPAP, 26+/-5; PCWP, 15+/-4; vitamin C: MPAP, 26+/-4; PCWP, 16+/-4), and platelet cGMP was significantly increased (placebo group: 2.42+/-0.24; vitamin C: 2.26+/-0.26). However, at 18 hours after titration, in the placebo group, MPAP (44+/-5) and PCWP (23+/-4) were increased, and platelet cGMP (0.85+/-0.20) and plasma vitamin E levels (12.4+/-1.4) were significantly decreased. In contrast, in the vitamin C group, MPAP (31+/-6), PCWP (17+/-5), platelet cGMP (2.49+/-0.23), and plasma vitamin E levels (17.6+/-1.4) were maintained for 18 hours after the titration period.
CONCLUSIONS: These findings indicate that ascorbate, an antioxidant, may prevent the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure.
Source: http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract
<H4>Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure</H4><I>
Hornig B, Arakawa N, Kohler C, Drexler H. Abteilung Kardiologie, Medizinische Hochschule Hannover, Germany.</I><BR>
BACKGROUND: Chronic heart failure (CHF) is associated with endothelial dysfunction including impaired endothelium-mediated, flow-dependent dilation (FDD). There is evidence for increased radical formation in CHF, raising the possibility that nitric oxide is inactivated by radicals, thereby impairing endothelial function. To test this hypothesis, we determined the effect of the antioxidant vitamin C on FDD in patients with CHF. METHODS AND RESULTS: High-resolution ultrasound and Doppler was used to measure radial artery diameter and blood flow in 15 patients with CHF and 8 healthy volunteers. Vascular effects of vitamin C (25 mg/min IA) and placebo were determined at rest and during reactive hyperemia (causing endothelium-mediated dilation) before and after intra-arterial infusion of N-monomethyl-L-arginine (L-NMMA) to inhibit endothelial synthesis of nitric oxide. Vitamin C restored FDD in patients with heart failure after acute intra-arterial administration (13.2+/-1.7% versus 8.2+/-1.0%; P<.01) and after 4 weeks of oral therapy (11.9+/-0.9% versus 8.2+/-1.0%; P<.05). In particular, the portion of FDD mediated by nitric oxide (ie, inhibited by L-NMMA) was increased after acute as well as after chronic treatment (CHF baseline: 4.2+/-0.7%; acute: 9.1+/-1.3%; chronic: 7.3+/-1.2%; normal subjects: 8.9+/-0.8%; P<.01).
CONCLUSIONS: Vitamin C improves FDD in patients with CHF as the result of increased availability of nitric oxide. This observation supports the concept that endothelial dysfunction in patients with CHF is, at least in part, due to accelerated degradation of nitric oxide by radicals.
Source: http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract
<H4>An experimental study on the protection against reperfusion myocardial ischemia by using large doses of vitamin C</H4><I>
CHIN. J. CARDIOL. (China), 1994, 22/1 (52-54+80) </I><BR>
To obtain the practical measure for the ischemia-reperfusion injury, we developed an open chest pig model (occlusion for 1 hour and reperfusion for 2 hours). Vitamin C (Vit C 0.2 g/kg) was intravenously given within five minutes to 8 pigs and 12 pigs received only saline as control. The results showed that there were no differences in the hemodynamic parameters, but the release of the creatine kinase isoenzyme after the reperfusion was significantly decreased in the vit C group (P < 0.05-0.01), and the ratio of the infarct area and the risk area was 30.2% in the vit C group and 49.2% in controls respectively (P < 0.05). Furthermore, the content of myocardial malondialdehyde was significantly decreased in the vit C group. In order to observe the protective effect of vitamin C we also developed an open chest rabbit model. After four-hour reperfusion, vit C group had less severe bleeding and milder damage to the capillary endothelium than that of control group. On the rabbit model, the myocardial free radicals were directly measured with the electron resonance spectrograph after one half hour reperfusion (P < 0.05). It was found that the free radical content was significantly elevated in the control group (P < 0.05), vit C could inhibit such elevation (P < 0.01). So it was evident that the protection of vit C was directly related to scavenging the free radicals.
http://www.lef.org/prod_hp/abstracts/php-ab421.html
<H4>Influence of vitamin C on baroreflex sensitivity in chronic heart failure</H4><I>
Piccirillo G, Nocco M, Moise A, Lionetti M, Naso C, di Carlo S, Marigliano V. Dipartimento di Scienze dell'Invecchiamento, I Clinica Medica, Policlinico Umberto I, Universita La Sapienza, 00161 Rome, Italy. gianfranco.piccirillo@uniroma1.it</I><BR>
Chronic heart failure (CHF) reduces baroreflex sensitivity. Low baroreflex sensitivity, a risk factor for sudden death, could arise partly from CHF-dependent endothelial dysfunction. Vitamin C at high doses has a protective role against CHF-related endothelial damage. This study was conducted to investigate the effect of vitamin C on baroreflex sensitivity in CHF. A study group of 33 subjects with CHF secondary to postischemic dilated cardiomyopathy with an ejection fraction </=35% and a control group (11 subjects) underwent assessment of baroreflex sensitivity by the phenylephrine method and an autonomic nervous system study by power spectral analysis. Variables were assessed after infusion of placebo and high doses of vitamin C (2.5 mg). In subjects with CHF, baroreflex sensitivity was significantly higher after vitamin C than after placebo infusion (placebo: 4.1+/-0.4 versus vitamin C: 5.3+/-0.5 ms/mm Hg, P<0.001). Low-frequency of R-R (LFRR), expressed in normalized units (NU) (P<0.05); LF/high-frequency (HF) ratio (P<0.05), and LF of SBP (LFSBP) decreased significantly; HF power (P<0.05), and alpha-HF (P<0.001) increased. Conversely, in the control group, baroreflex sensitivity and other spectral variables measured at baseline, after placebo, and after vitamin C infusion remained statistically unchanged (placebo: 10.2+/-0.1 versus vitamin C: 10.0+/-0.2 ms/mm Hg, NS). Acute administration of vitamin C at high doses improves baroreflex sensitivity and vagal sinus modulation in patients with CHF. This finding could have notable clinical and therapeutic implications. Key issues to understand are whether the beneficial effect persists during chronic administration and whether it helps to improve survival.
Source: http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract
<H4>Antioxidant vitamins attenuate oxidative stress and cardiac dysfunction in tachycardia-induced cardiomyopathy</H4><I>
Shite J, Qin F, Mao W, Kawai H, Stevens SY, Liang C. Cardiology Unit, Department of Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA.</I><BR>
OBJECTIVES: We administered antioxidant vitamins to rabbits with pacing-induced cardiomyopathy to assess whether antioxidant therapy retards the progression of congestive heart failure (CHF). BACKGROUND: Although oxidative stress is increased in CHF, whether progression of heart failure could be prevented or reduced by antioxidants is not known. METHODS: Rabbits with chronic cardiac pacing and sham operation were randomized to receive a combination of beta-carotene, ascorbic acid and alpha-tocopherol, alpha-tocopherol alone or placebo over eight weeks. Echocardiography was used to measure cardiac function weekly. Resting hemodynamics and in vivo myocardial beta-adrenergic responsiveness were studied at week 8. Animals were then sacrificed for measuring myocardial beta-receptor density, norepinephrine (NE) uptake-1 site density, sympathetic neuronal marker profiles, tissue-reduced glutathione/oxidized glutathione (GSH/GSSG) ratio and oxidative damage of mitochondrial DNA (mtDNA). RESULTS: Rapid cardiac pacing increased myocardial oxidative stress as evidenced by reduced myocardial GSH/GSSG ratio and increased oxidized mtDNA and produced cardiac dysfunction, beta-adrenergic subsensitivity, beta-receptor downregulation, diminished sympathetic neurotransmitter profiles and reduced NE uptake-1 carrier density. A combination of antioxidant vitamins reduced the myocardial oxidative stress, attenuated cardiac dysfunction and prevented myocardial beta-receptor downregulation and sympathetic nerve terminal dysfunction. Administration of alpha-tocopherol alone produced similar effects, but the effects were less marked than those produced by the three vitamins together. Vitamins produced no effects in sham-operated animals.
CONCLUSIONS: Antioxidant vitamins reduced tissue oxidative stress in CHF and attenuated the associated cardiac dysfunction, beta-receptor downregulation and sympathetic nerve terminal abnormalities. The findings suggest that antioxidant therapy may be efficacious in human CHF.
Source: http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract
<H4>The protective effects of high dose ascorbic acid and diltiazem on myocardial ischaemia-reperfusion injury</H4><I>
Demirag K, Askar FZ, Uyar M, Cevik A, Ozmen D, Mutaf I, Bayindir O. Dept of Anesthesiology Ege University, Faculty of Medicine, Bornova, 35100 Izmir, Turkey.</I><BR>
In this study, we aimed to compare the myocardial protective effects of high dose ascorbic acid with the effects obtained by adding diltiazem to high dose ascorbic acid. We studied 30 elective cardiac surgery patients prospectively. In ascorbic acid group (group AA), ascorbic acid was given after induction and just before aortic declamping, 50 mg.kg-1 each time. In ascorbic acid + diltiazem group (group AA + D), diltiazem was added to ascorbic acid (0.3 mg.kg-1, i.v. after induction and then 2 micrograms.kg-1 min-1 i.v. infusion until declamping). Group C was the control group. There was no significant difference between groups in terms of cardiac enzyme levels. After declamping, the arterial and coronary sinus malondialdehyde levels, measured as a marker of lipid peroxidation, were increased significantly in the group C while remained stable in the other two groups. Ventricular fibrillation (VF) after declamping was positive in 3, 1 and 6 patients in the groups AA, AA + D and C respectively. In this study, we observed the prevention of lipid peroxidation in the group AA and group AA + D. The only positive result obtained by addition of diltiazem to high dose ascorbic acid was the decrease in the frequency of VF after declamping. We concluded that the prevention of lipid peroxidation in the groups AA and AA + D provided no measurable protection over myocardial ischaemia-reperfusion injury.
Source: http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract
<H4>Acute effects of vitamin C on platelet responsiveness to nitric oxide donors and endothelial function in patients with chronic heart failure</H4><I>
Ellis GR, Anderson RA, Chirkov YY, Morris-Thurgood J, Jackson SK, Lewis MJ, Horowitz JD, Frenneaux MP. Cardiovascular Sciences Research Group, Wales Heart Research Institute, University of Wales College of Medicine, Cardiff, UK. grellis@doctorsorg.co.uk</I><BR>
Chronic heart failure (CHF) is characterized by a prothrombotic state, which may relate to increased platelet aggregability, endothelial dysfunction, and increased oxidative stress. We investigated the effect of vitamin C in CHF on ex vivo platelet aggregation and platelet responsiveness to the anti-aggregatory effects of the nitric oxide (NO) donors glyceryl trinitrate (GTN) and sodium nitroprusside (SNP). We also examined parameters of oxidative stress and endothelial function in patients. In this double-blind, randomized, crossover study vitamin C (2 g) or placebo was given intravenously to 10 patients with CHF. We measured adenosine 5-diphosphate (ADP)-induced platelet aggregation, flow-mediated dilatation (FMD) in the brachial artery using ultrasonic wall-tracking, and plasma levels of lipid-derived free radicals using electron paramagnetic resonance spectroscopy. Vitamin C did not affect ex vivo platelet aggregability but enhanced the inhibition of platelet aggregation by SNP (62.7+/-10.2 to 82.7+/-4.8%, p = 0.03) and tended to increase responses to GTN (40.5+/-9.0 to 53.4+/-7.3, p = 0.06). The effect of vitamin C on platelet responsiveness to the antiaggregatory effects of SNP was inversely related to basal response to SNP (r = -0.9, p < 0.01); a similar trend was observed with GTN (r = -0.6, p = 0.1). Vitamin C also increased FMD (1.9+/-0.6 to 5.8+/-1.5%, p = 0.02) and reduced plasma lipid-derived free radicals by 49+/-19% (p < 0.05). In patients with CHF acute intravenous administration of vitamin C enhances platelet responsiveness to the anti-aggregatory effects of NO donors and improves endothelial function, suggesting a potential role for vitamin C as a therapeutic agent in CHF.
Source: http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract
<H4>Fatal cyclophosphamide cardiomyopathy: its clinical course and treatment</H4><I>
Lee CK, Harman GS, Hohl RJ, Gingrich RD. College of Medicine, Department of Internal Medicine, University of Iowa, USA.</I><BR>
Acute decompensating cardiomyopathy induced by cyclophosphamide is usually irreversible. To investigate the clinical course and the outcome of therapy, 13 patients (1.7%) with grade III acute cardiomyopathy and hypotension who were treated with ablative transplant regimens between January 1980 and September 1995 were analyzed. Eight of nine patients died of acute fatal restrictive cardiomyopathy with unresponsive hypotension (ARCH), whereas three of four patients who survived the initial episode died of subacute congestive heart failure (SCHF). Acute fatal restrictive cardiomyopathy was characterized with extreme sensitivity to volume overload, myocardial edema and a rapidly fatal course. It was associated with progressive, unresponsive hypotension, reduced left ventricular stroke work index (LVSWI: 29.29 +/- 9.74 g-m/beat/m2) and markedly reduced systemic and pulmonary vascular resistance indices (SVRI: 429.72 +/- 168.84, PVRI: 58.63 +/- 45.08 dyne.sec/cm5.m2). Subacute CHF was identified by myocardial edema, dilated chambers and biventricular pump failure represented by decreases in fractional shortening (FS: 19.5 +/- 4.9%). Of 10 patients who received conventional therapy, nine died and one sustained chronic CHF. One of three patients with ARCH on antioxidant therapy of ascorbic acid and theophylline survived the episode. The data suggests peripheral vascular collapse may also be responsible for fatal ARCH.
Source: http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

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